Neurofibromatosis type 1: Its association with the Ras/MAPK pathway syndromes

摘要: Neurofibromatosis type 1 (NF1) is a common (affects ∼1 in 4000 individuals worldwide) autosomal dominant neurocutaneous syndrome, resulting from functional inactivation of the NF1 gene. The main clinical features include dermal pigmentary changes (cafe-au-lait spots and skin fold freckling), development benign peripheral nerve sheath-derived tumors (neurofibromas) hamartomas iris (Lisch nodules). Benign tumor development, involving nerves central nervous system, are hallmark NF1. Associated manifestations can abnormalities cardiovascular, gastrointestinal, renal endocrine systems, orthopedic problems, macrocephaly, small stature, facial body dysmorphism, learning disabilities, an increased malignancy risk. Neurofibromin, gene product, mammalian Ras GTPase-activating protein expressed most tissues, with leading to cellular signaling, cell growth, proliferation tumorigenesis, underlining its role as suppressor At least 1050 different disease-causing mutations known, although correlating specific has proved largely unsuccessful, only two such associations identified. One relating severely affected patients large genomic deletions that involve entire gene, other, some mildly without any cutaneous neurofibromas, who have same 3bp deletion. Several animal models been developed allowed analysis crucial unravelling complexity signaling pathway regulating proliferation, differentiation, motility, apoptosis tumorigenesis. Such also better defined probable causes NF1-related difficulties, skeletal abnormalities, identified neurofibromin cyclic AMP regulator. It now recognized number genes complex RAS-MAPK associated several neuro-cardio-facial-cutaneous syndromes, group pheno- genotypically similar developmental disorders, includes recent identification SPRED1 mild NF1-like extends this disease association spred proteins known be directly involved pathway. No effective treatment for currently available, many proposed therapies, often aimed at preventing showing little success, statin-based useful treating mouse model disability tibial dysplasia. therapies targeting mast function, components, well growth factor receptors, may hopefully prove more successful.